N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B

ABSTRACT

Inhibitors of HBV replication of Formula (I) 
                         
including stereochemically isomeric forms, and salts, hydrates, solvates thereof, wherein X, R 1 , R 2 , R 3  and R 4  have the meaning as defined herein.
 
     The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use, alone or in combination with other HBV inhibitors, in HBV therapy.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a 35 U.S.C. § 371 nationalization of PCT application PCT/EP2014/056601 filed Apr. 2, 2014, which claims priority to European patent application EP 13162131.0 filed Apr. 3, 2013, each of which are incorporated herein by reference in its entirety.

BACKGROUND ART

The Hepatitis B virus (HBV) is an enveloped, partially double-stranded DNA (dsDNA) virus of the Hepadnavirus family (Hepadnaviridae). Its genome contains 4 overlapping reading frames: the precore/core gene; the polymerase gene; the L, M, and S genes, which encode for the 3 envelope proteins; and the X gene.

Upon infection, the partially double-stranded DNA genome (the relaxed circular DNA; rcDNA) is converted to a covalently closed circular DNA (cccDNA) in the nucleus of the host cell and the viral mRNAs are transcribed. Once encapsidated, the pregenomic RNA (pgRNA), which also codes for core protein and Pol, serves as the template for reverse transcription, which regenerates the partially dsDNA genome (rcDNA) in the nucleocapsid.

HBV has caused epidemics in parts of Asia and Africa, and it is endemic in China. HBV has infected approximately 2 billion people worldwide of which approximately 350 million people have developed chronic infections. The virus causes the disease hepatitis B and chronic infection is correlated with a strongly increased risk for the development cirrhosis and hepatocellular carcinoma.

Transmission of hepatitis B virus results from exposure to infectious blood or body fluids, while viral DNA has been detected in the saliva, tears, and urine of chronic carriers with high titer DNA in serum.

An effective and well-tolerated vaccine exists, but direct treatment options are currently limited to interferon and the following antivirals; tenofovir, lamivudine, adefovir, entecavir and telbivudine.

In addition, heteroaryldihydropyrimidines (HAPs) were identified as a class of HBV inhibitors in tissue culture and animal models (Weber et al., Antiviral Res. 54: 69-78).

WO/2013/006394, published on Jan. 10 2013, relates to a subclass of Sulphamoyl-arylamides active against HBV.

Amongst the problems which HBV direct antivirals may encounter are toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, and difficulty of synthesis.

There is a need for additional HBV inhibitors that may overcome at least one of these disadvantages or that have additional advantages such as increased potency or an increased safety window.

DESCRIPTION OF THE INVENTION

The present invention relates to a compound of Formula (I)

or a stereoisomer or tautomeric form thereof, wherein:

represents:

-   X represents —(SO₂)— or a single bond, wherein, -   When X represents —(SO₂)—:     -   R⁴ is selected from the group consisting of —NR⁵R⁶, C₁-C₆alkyl,         and a 3-7 membered saturated ring optionally containing one or         more heteroatoms each independently selected from the group         consisting of O, S and N, such 3-7 membered saturated ring or         C₁-C₆alkyl optionally being substituted with one or more         substituents each independently selected from the group         consisting of hydrogen, fluoro, C₁-C₄alkyloxy, OH, oxo,         C₁-C₄alkyl, and cyclopropyl, and R¹, R² and R³ are independently         selected from the group consisting of Hydrogen, Halogen, CN,         Chloro, CHF₂, CH₂F, CF₃ and C₁-C₃alkyl and cyclopropyl; -   When X represents a single bond:     -   R⁴ is —C(═O)O—R²,     -   and R¹, R² and R³ are independently selected from the group         consisting of Hydrogen, Halogen, CN, Chloro, CHF₂, CH₂F, CF₃ and         C₁-C₃alkyl and cyclopropyl; such that at least one of R¹, R² and         R³ is Fluor, and one other of R¹, R² and R³ is Hydrogen,         Halogen, CN, Chloro, CHF₂, CH₂F, CF₃ and C₁-C₃alkyl and         cyclopropyl; -   R⁵ is selected from the group consisting of Hydrogen or methyl; -   R⁶ is selected from the group consisting of C₁-C₆alkyl or a 3-7     membered saturated ring optionally containing one or more     heteroatoms each independently selected from the group consisting of     O, S and N, such 3-7 membered saturated ring or C₁-C₆alkyl     optionally being substituted with one or more substituents each     independently selected from the group consisting of hydrogen,     fluoro, CN, OH, oxo, —NHC(═O)O—C₁-C₄alkyl, C₁-C₄alkyl optionally     substituted with R⁸, C₁-C₄alkyloxy,

-   R⁷ is selected from the group consisting of C₁-C₆alkyl or a 3-7     membered saturated ring optionally containing one or more     heteroatoms each independently selected from the group consisting of     O, S and N; -   R⁸ is selected from the group consisting hydrogen, OH, C₁-C₄alkyl or     CN;     or a pharmaceutically acceptable salt or a solvate thereof.

The invention further relates to a pharmaceutical composition comprising a compound of Formula (I), and a pharmaceutically acceptable carrier.

The invention also relates to the compounds of Formula (I) for use as a medicament, preferably for use in the prevention or treatment of an HBV infection in a mammal.

In a further aspect, the invention relates to a combination of a compound of Formula (I), and another HBV inhibitor.

Definitions

The term “C₁₋₃alkyl” as a group or part of a group refers to a hydrocarbyl radical of Formula C_(n)H_(2n+1) wherein n is a number ranging from 1 to 3. In case C₁₋₃alkyl is coupled to a further radical, it refers to a Formula C_(n)H_(2n). C₁₋₃alkyl groups comprise from 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. C₁₋₃alkyl includes all linear, or branched alkyl groups with between 1 and 3 carbon atoms, and thus includes such as for example methyl, ethyl, n-propyl, and i-propyl.

C₁₋₄alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as the group defined for C₁₋₃alkyl and butyl and the like.

C₁₋₆alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the groups defined for C₁₋₄alkyl and pentyl, hexyl, 2-methylbutyl and the like.

The term “C₁₋₃alkyloxy” as a group or part of a group refers to a radical having the Formula —OR^(c) wherein R^(c) is C₁₋₃alkyl. Non-limiting examples of suitable C₁₋₃alkyloxy include methyloxy (also methoxy), ethyloxy (also ethoxy), propyloxy and isopropyloxy.

The term oxo, C(═O), or carbonyl refers to a group composed of a carbon atom double bonded to an oxygen atom.

As used herein, the term “3-7 membered saturated ring” means saturated cyclic hydrocarbon with 3, 4, 5, 6 or 7 carbon atoms and is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Such saturated ring optionally contains one or more heteroatoms, such that at least one carbon atom is replaced by a heteroatom selected from N, O and S, in particular from N and O.

Examples include oxetane, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, thiolane 1,1-dioxide and pyrrolidinyl. Preferred are saturated cyclic hydrocarbon with 3 or 4 carbon atoms and 1 oxygen atom. Examples include oxetane, and tetrahydrofuranyl.

It should be noted that different isomers of the various heterocycles may exist within the definitions as used throughout the specification. For example, pyrrolyl may be 1H-pyrrolyl or 2H-pyrrolyl.

The term halo and halogen are generic to fluoro, chloro, bromo or iodo. Preferred halogens are fluoro and chloro.

It should also be noted that the radical positions on any molecular moiety used in the definitions may be anywhere on such moiety as long as it is chemically stable. For instance pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl includes 1-pentyl, 2-pentyl and 3-pentyl.

Positions indicated on phenyl (e.g. ortho, meta and/or para) are indicated relative to the bond connecting the phenyl to the main structure. An example with regard to the position of R¹, any location is indicated relative to the nitrogen (*) connected to the main structure:

When any variable (e.g. halogen or C₁₋₄alkyl) occurs more than one time in any constituent, each definition is independent.

For therapeutic use, the salts of the compounds of formula (I) are those wherein the counter ion is pharmaceutically or physiologically acceptable. However, salts having a pharmaceutically unacceptable counter ion may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound of formula (I). All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.

The pharmaceutically acceptable or physiologically tolerable addition salt forms which the compounds of the present invention are able to form can conveniently be prepared using the appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; hemisulphuric, nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, aspartic, dodecylsulphuric, heptanoic, hexanoic, nicotinic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

Conversely said acid addition salt forms can be converted by treatment with an appropriate base into the free base form.

The term “salts” also comprises the hydrates and the solvent addition forms that the compounds of the present invention are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.

The present compounds may also exist in their tautomeric forms For example, tautomeric forms of amide (—C(═O)—NH—) groups are iminoalcohols (—C(OH)═N—). Tautomeric forms, although not explicitly indicated in the structural formulae represented herein, are intended to be included within the scope of the present invention.

The term stereochemically isomeric forms of compounds of the present invention, as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of the present invention may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of the present invention both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.

Pure stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term ‘stereoisomerically pure’ concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i e minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%. The terms ‘enantiomerically pure’ and ‘diastereomerically pure’ should be understood in a similar way, but then having regard to the enantiomeric excess, respectively the diastereomeric excess of the mixture in question.

Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application of art-known procedures. For instance, enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphosulfonic acid. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

The diastereomeric forms of formula (I) can be obtained separately by conventional methods. Appropriate physical separation methods that may advantageously be employed are, for example, selective crystallization and chromatography, e.g. column chromatography.

The present invention is also intended to include all isotopes of atoms occurring on the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

DETAILED DESCRIPTION OF THE INVENTION

Whenever used hereinafter, the term “compounds of formula (I)”,

or “the present compounds” or similar term is meant to include the compounds of general formula (I), (Ib), salts, stereoisomeric forms and racemic mixtures or any subgroups thereof.

Compounds for use in the prevention or treatment of an HBV infection in a mammal are disclosed as compounds per se and not limited to this use unless restricted by the claims.

In a first aspect, the invention provides compound of Formula (I)

or a stereoisomer or tautomeric form thereof, wherein:

represents:

-   X represents —(SO₂)— or a single bond, wherein, -   When X represents —(SO₂)—:     -   R⁴ is selected from the group consisting of —NR⁵R⁶, C₁-C₆alkyl,         and a 3-7 membered saturated ring optionally containing one or         more heteroatoms each independently selected from the group         consisting of O, S and N, such 3-7 membered saturated ring or         C₁-C₆alkyl optionally being substituted with one or more         substituents each independently selected from the group         consisting of hydrogen, fluoro, C₁-C₄alkyloxy, OH, oxo,         C₁-C₄alkyl, and cyclopropyl, and R¹, R² and R³ are independently         selected from the group consisting of Hydrogen, Halogen, CN,         Chloro, CHF₂, CH₂F, CF₃ and C₁-C₃alkyl and cyclopropyl; -   When X represents a single bond:     -   R⁴ is —C(═O)O—R²,     -   and R¹, R² and R³ are independently selected from the group         consisting of Hydrogen, Halogen, CN, Chloro, CHF₂, CH₂F, CF₃ and         C₁-C₃alkyl and cyclopropyl; such that at least one of R¹, R² and         R³ is Fluor, and one other of R¹, R² and R³ is Hydrogen,         Halogen, CN, Chloro, CHF₂, CH₂F, CF₃ and C₁-C₃alkyl and         cyclopropyl; -   R⁵ is selected from the group consisting of Hydrogen or methyl; -   R⁶ is selected from the group consisting of C₁-C₆alkyl or a 3-7     membered saturated ring optionally containing one or more     heteroatoms each independently selected from the group consisting of     O, S and N, such 3-7 membered saturated ring or C₁-C₆alkyl     optionally being substituted with one or more substituents each     independently selected from the group consisting of hydrogen,     fluoro, CN, OH, oxo, —NHC(═O)O—C₁-C₄alkyl, C₁-C₄alkyl optionally     substituted with R⁸, C₁-C₄alkyloxy,

-   R⁷ is selected from the group consisting of C₁-C₆alkyl or a 3-7     membered saturated ring optionally containing one or more     heteroatoms each independently selected from the group consisting of     O, S and N; -   R⁸ is selected from the group consisting hydrogen, OH, C₁-C₄alkyl or     CN;     or a pharmaceutically acceptable salt or a solvate thereof.

In a further aspect, the invention relates to compounds of Formula (I)

or a stereoisomer or tautomeric form thereof, wherein:

represents:

-   X represents —(SO₂)— or a single bond wherein, -   When X represents —(SO₂)—;     -   R⁴ is selected from the group consisting of —NR⁵R⁶, C₁-C₆alkyl,         and a 3-7 membered saturated ring optionally containing one or         more heteroatoms each independently selected from the group         consisting of O, S and N, such 3-7 membered saturated ring or         C₁-C₆alkyl optionally being substituted with one or more         substituents each independently selected from the group         consisting of hydrogen, fluoro, C₁-C₄alkyloxy, OH, oxo,         C₁-C₄alkyl, and cyclopropyl,     -   and R¹, R² and R³ are independently selected from the group         consisting of Hydrogen, Fluor, Chloro, CHF₂, CH₂F, CF₃ and         methyl; -   When X represents a single bond:     -   R⁴ is —C(═O)O—R⁷,     -   and R¹, R² and R³ are independently selected from the group         consisting of Hydrogen, Fluor, Chloro, CHF₂, CH₂F, CF₃ and         methyl, such that at least one of R¹, R² and R³ is Fluor, and         one other of R¹, R² and R³ is Fluor, CHF₂, CH₂F, CF₃ or methyl. -   R⁵ is selected from the group consisting of Hydrogen or methyl; -   R⁶ is selected from the group consisting of C₁-C₆alkyl or a 3-7     membered saturated ring optionally containing one or more     heteroatoms each independently selected from the group consisting of     O, S and N, such 3-7 membered saturated ring or C₁-C₆alkyl     optionally being substituted with one or more substituents each     independently selected from the group consisting of hydrogen, or     C₁-C₄alkyl; -   R⁷ is selected from the group consisting of C₁-C₆alkyl or a 3-7     membered saturated ring optionally containing one or more     heteroatoms each independently selected from the group consisting of     O, S and N;     or a pharmaceutically acceptable salt or a solvate thereof.

In one embodiment of the present invention,

represents

In a further embodiment of the present invention, compounds are represented by Formula (Ib)

or a stereoisomer or tautomeric form, or pharmaceutically acceptable salts or a solvate thereof.

In a preferred embodiment, compounds of Formula (I) or (Ib) are envisioned wherein R¹ is selected from either Fluor or methyl, and R² is Fluor.

In yet another embodiment, compounds of Formula (I) or (Ib) are envisioned wherein X is —(SO₂)—, R⁴ is NR⁵R⁶ and R⁵ and R⁶ are as defined above.

In a further embodiment, compounds of Formula (I) or (Ib) are envisioned wherein R⁴ contains a 3-7 membered saturated ring optionally containing one oxygen.

Another embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein one or more of the following restriction applies:

-   -   (a) R⁶ is C₁-C₆alkyl optionally being substituted with one or         more Fluoro.     -   (b) R¹ is methyl.     -   (c) R² and R³ are independently selected from the group         consisting of Hydrogen, Fluoro and methyl.     -   (d) R⁶ contains a 3-7 membered saturated ring optionally         containing one oxygen, more specifically R⁶ is a 4 or 5 membered         saturated ring containing one oxygen, such 4 or 5 membered         saturated ring optionally substituted with methyl.     -   (e) R⁶ comprises a branched C₃-C₆alkyl optionally substituted         with one or more Fluoro, or R⁶ comprises a C₃-C₆cycloalkyl         wherein such C₃-C₆cycloalkyl is substituted with one or more         Fluoro or substituted with C₁-C₄ substituted with one or more         Fluoro. More specifically, R⁶ is a branched C₃-C₆alkyl         substituted with one or more Fluoro.     -   (f) R⁶ is selected from the group consisting of C₂-C₆alkyl         optionally being substituted with one or more Fluoro.

Further combinations of any of the sub- or preferred embodiments are also envisioned to be in the scope of the present invention.

Preferred compounds according to the invention are compound or a stereoisomer or tautomeric form thereof with a formula selected from table 1.

In a further aspect, the present invention concerns a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound of Formula (I) as specified herein, and a pharmaceutically acceptable carrier. A prophylactically effective amount in this context is an amount sufficient to prevent HBV infection in subjects being at risk of being infected. A therapeutically effective amount in this context is an amount sufficient to stabilize HBV infection, to reduce HBV infection, or to eradicate HBV infection, in infected subjects. In still a further aspect, this invention relates to a process of preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically or prophylactically effective amount of a compound of Formula (I), as specified herein.

Therefore, the compounds of the present invention or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. The compounds of the present invention may also be administered via oral inhalation or insufflation in the form of a solution, a suspension or a dry powder using any art-known delivery system.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.

The compounds of Formula (I) are active as inhibitors of the HBV replication cycle and can be used in the treatment and prophylaxis of HBV infection or diseases associated with HBV. The latter include progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease, and hepatocellular carcinoma.

Due to their antiviral properties, particularly their anti-HBV properties, the compounds of Formula (I) or any subgroup thereof, are useful in the inhibition of the HBV replication cycle, in particular in the treatment of warm-blooded animals, in particular humans, infected with HBV, and for the prophylaxis of HBV infections. The present invention furthermore relates to a method of treating a warm-blooded animal, in particular human, infected by HBV, or being at risk of infection by HBV, said method comprising the administration of a therapeutically effective amount of a compound of Formula (I).

The compounds of Formula (I), as specified herein, may therefore be used as a medicine, in particular as medicine to treat or prevent HBV infection. Said use as a medicine or method of treatment comprises the systemic administration to HBV infected subjects or to subjects susceptible to HBV infection of an amount effective to combat the conditions associated with HBV infection or an amount effective to prevent HBV infection.

The present invention also relates to the use of the present compounds in the manufacture of a medicament for the treatment or the prevention of HBV infection.

In general it is contemplated that an antiviral effective daily amount would be from about 0.01 to about 50 mg/kg, or about 0.01 to about 30 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing about 1 to about 500 mg, or about 1 to about 300 mg, or about 1 to about 100 mg, or about 2 to about 50 mg of active ingredient per unit dosage form.

The present invention also concerns combinations of a compound of formula (I) or any subgroup thereof, as specified herein with other anti-HBV agents. The term “combination” may relate to a product or kit containing (a) a compound of Formula (I), as specified above, and (b) at least one other compound capable of treating HBV infection (herein designated as anti-HBV agent), as a combined preparation for simultaneous, separate or sequential use in treatment of HBV infections. In an embodiment, the invention concerns combination of a compound of formula (I) or any subgroup thereof with at least one anti-HBV agent. In a particular embodiment, the invention concerns combination of a compound of formula (I) or any subgroup thereof with at least two anti-HBV agents. In a particular embodiment, the invention concerns combination of a compound of formula (I) or any subgroup thereof with at least three anti-HBV agents. In a particular embodiment, the invention concerns combination of a compound of formula (I) or any subgroup thereof with at least four anti-HBV agents.

The combination of previously known anti-HBV agents, such as interferon-α (IFN-α), pegylated interferon-α, 3TC, adefovir or a combination thereof, and, a compound of formula (I) or any subgroup thereof can be used as a medicine in a combination therapy.

Generic Synthesis:

The substituents represented in this general synthesis section are meant to include any substituent or reactive species that is suitable for transformation into any substituent according to the present invention without undue burden for the person skilled in the art.

The general synthesis of compound of Formula (I) is described in scheme 1 and scheme 2. As described in scheme 1, an amino acid of general Formula (II) is reacted with a reagent of general formula R⁴—X—Y, examples of such reagents with general formula R⁴—X—Y, in the context of scheme 1, are, but are not limited to, ClC(═O)O—R⁷,

and R⁴SO₂Cl, in the presence of a base like for example DIPEA. The resulting carboxylic acid III is reacted with an aniline of general formula (IV), for example under typical amide formation conditions like for example under the influence of HATU and DIPEA in CH₂Cl₂ at room temperature, resulting in compounds of general Formula (I).

Another possible synthetic route to compounds of general Formula (I) is described in scheme 2. In this case, compound V, an amino acid with a protection group PG on nitrogen, where PG for example can be Boc (tert-Butoxy)carbonyl) or Cbz (Benzyloxycarbonyl), is reacted with an aniline compound of general Formula (IV), under typical amide formation conditions, like for example under the influence of HATU and DIPEA in CH₂Cl₂. The resulting compound of general formula VI is deprotected, for example by treatment with HCl in iPrOH/CH₂Cl₂ or TFA in CH₂Cl₂ in case PG equals Boc, resulting in a compound of general formula VII. Further reaction of compound of general VII with a reagents of general formula R₄—X—Y (examples of R₄—X—Y in the context of scheme 2, are, but are not limited to, ClC(═O)O—R⁷, R₄SO₂Cl and

possibly in the presence of a base like for example NEt₃, results in compounds of general Formula (I).

An other possible route to compound of general Formula (I)c is described in scheme 3. A compound of general formula VII is reacted with a reagent of general formula VIII. Examples of such reagent VIII are, but are not limited to NH₂SO₂NH₂ and

In case of

reaction with VII is followed by a methylation with for example MeOTf, resulting in a compound of general Formula (IXa):

Further reaction with an amine of general formula XI, results in the formation of a compound of general Formula (Ic).

General Procedure LCMS Methods

The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below). Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time . . . ) in order to obtain ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software.

Compounds are described by their experimental retention times (R_(t)) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]⁺ (protonated molecule) and/or [M−H]⁻ (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH₄]⁺, [M+HCOO]⁻, etc. . . . ). All results were obtained with experimental uncertainties that are commonly associated with the method used.

Hereinafter, “SQD” means Single Quadrupole Detector, “MSD” Mass Selective Detector, “RT” room temperature, “BEH” bridged ethylsiloxane/silica hybrid, “DAD” Diode Array Detector, “HSS” High Strength silica, “Q-Tof” Quadrupole Time-of-flight mass spectrometers, “CLND”, ChemiLuminescent Nitrogen Detector, “ELSD” Evaporative Light Scanning Detector,

LCMS Methods (Flow expressed in mL/min; column temperature (T) in ° C.; Run time in minutes).

Method Mobile Flow Run LCMS Instrument Column phase Gradient Col T time A Agilent 1100- YMC-PACK A: 0.1% TFA in 100% A held for 0.8 10.0 UV 220 nm ODS-AQ, H₂O 1 min from 100% 50 50 × 2.0 mm B: 0.05 TFA in A to 40% A in 4 5 μm CH₃CN min, held for 2.5 min, to 100% A in 0.5 min held for 2 min. B Agilent 1100- XBridge A: 0.05% NH₃ in 100% A held for 0.8 10.0 UV 220 nm ShieldRP18, H₂O 1 min from 100% 40 50 * 2.1 mm B: CH₃CN to 40% A in 4 5 μm min, held for 2.5 min, to 100% A in 0.5 min held for 2 min. C Waters: Waters : BEH in A: 10 mM From 95% A to 0.8 2 Acquity ® C18 (1.7 μm, CH₃COONH₄ in 5% A in 1.3 min, 55 UPLC ®-DAD 2.1 * 50 mm) 95% H₂O + 5% held for 0.7 min. and SQD CH₃CN B: CH₃CN D Agilent 1100- YMC-PACK A: 0.1% TFA in 70% A held for 0.8 10.0 UV 220 nm ODS-AQ, H₂O 0.8 min from 70% 50 50 × 2.0 mm B: 0.05 TFA in to 10% A in 3.2 5 μm CH₃CN min, held for 2.5 min, to 70% A in 0.5 min held for 2 min. E Waters: Waters : HSS A: 10 mM From 100% A to 0.8 3.5 Acquity ® T3 (1.81 μm, CH₃COONH₄ in 5% A in 2.10 min, 55 UPLC ®-DAD 2.1 * 100 mm) 95% H₂O + 5% to 0% A in 0.90 and SQD CH₃CN min, to 5% A in B: CH₃CN 0.5 min Synthesis of Compounds:

Compound 1: N-(4-fluoro-3-methyl-phenyl)-1-isobutylsulfonyl-pyrrolidine-3-carboxamide

To a stirred solution of 4-fluoro-3-methyl-aniline (2.0 g, 15.98 mmol), 1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (3.44 g, 15.98 mmol) and DIPEA (6.2 g, 47.9 mmol) in CH₂Cl₂ (30 mL), HATU (7.29 g, 19.2 mmol) was added at 0° C. The resulting mixture was stirred at 18° C. overnight. The reaction mixture was washed with 1N HCl (30 mL) and saturated aqueous NaHCO₃ (30 mL), dried over Na₂SO₄ and concentrated in vacuo, resulting in tert-butyl-3-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrolidine-1-carboxylate (3.1 g). To a solution of tert-butyl 3-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrolidine-1-carboxylate (3.1 g, 9.62 mmol) in CH₂Cl₂ (30 mL), trifluoroacetic (20 mL) acid was added. The resulting mixture was stirred at 18° C. for 3 hours. The reaction mixture was adjusted to pH=7-8 with saturated aqueous NaHCO₃. The organic layer was separated, washed with brine and dried over Na₂SO₄. The solvent was removed in vacuo and the obtained residue (1.8 g) was used as such in the next step. To part of the above obtained residue (500 mg) and DIPEA (576 mg, 4.46 mmol) in CH₂Cl₂ (10 mL), 2-methylpropane-1-sulfonyl chloride (257 mg, 1.64 mmol) was added at 0° C. The resulting mixture was stirred at 18° C. for 4 hours. The reaction mixture was washed with 1N HCl (15 mL) and saturated aqueous NaHCO₃ (15 mL), dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by reversed phase preparative high-performance liquid chromatography (eluent: CH₃CN in H₂O (0.05% NH₃.H₂O) from 40% to 70%, v/v). The pure fractions were collected and the volatiles were removed in vacuo. The aqueous layer was lyophilized to dryness, resulting in compound 1 (40 mg).

Synthesis of Enantiomers of Compound 1 Compound 2: (3S)—N-(4-fluoro-3-methyl-phenyl)-1-isobutylsulfonyl-pyrrolidine-3-carboxamide

Prepared similarly as described for compound 1, starting from (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid instead of 1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid. Method A; Rt: 5.43 min. m/z: 343.3 (M+H)⁺ Exact mass: 342.1. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.8 Hz, 6H) 2.22-2.37 (m, 6H) 2.83-3.00 (m, 2H) 3.10 (quin, J=7.3 Hz, 1H) 3.42-3.59 (m, 3H) 3.73 (dd, J=10.0, 7.5 Hz, 1H) 6.94 (t, J=8.9 Hz, 1H) 7.22-7.30 (m, 1H) 7.36-7.41 (m, 1H) 7.73 (br. s, 1H). [α]₃₆₅ ²⁰: +9.7° (c 0.26 w/v %, DMF).

Compound 3: (3R)—N-(4-fluoro-3-methyl-phenyl)-1-isobutylsulfonyl-pyrrolidine-3-carboxamide

Prepared similarly as described for compound 1, starting from (3R)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid instead of 1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid. Method B; Rt: 5.54 min. m/z: 343.3 (M+H)+ Exact mass: 342.1. [α]₃₆₅ ²⁰: −12.5° (c 0.46 w/v %, DMF)

Synthesis of (3S)—N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide hydrochloride

4-fluoro-3-methylaniline (5.81 g, 46.5 mmol), Boc-(3S)-1-pyrrolidine-3-carboxylic acid (10 g, 46.5 mmol) and DIPEA (24 mL, 139.4 mmol) were dissolved in CH₂Cl₂ (30 mL). HATU (21.2 g, 55.7 mmol) was added in small portions and the resulted mixture was stirred overnight at room temperature. The reaction mixture was washed with 1M HCl (20 mL) and the organic layer was evaporated to dryness. The residue was purified by silica gel chromatography using a heptane to EtOAc gradient yielding tert-butyl (3S)-3-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrolidine-1-carboxylate as a light brown oil (14.7 g). (3S)-3-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrolidine-1-carboxylate (14.7 g) was dissolved in CH₂Cl₂ (100 mL) and HCl (6 M in iPrOH, 76 mL) was added. The reaction mixture was stirred overnight at room temperature. The volatiles were removed under reduced pressure and the obtained residue was triturated in diethylether, filtered and dried in vacuo overnight, yielding (3S)—N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide hydrochloride as a powder (11.2 g).

General Synthetic Procedure A:

(3S)—N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide hydrochloride (200 mg, 0.77 mmol) and DIPEA (2.5 eq) were dissolved in CH₂Cl₂ (5 mL). Reagent A (procedure A1: 0.140 mL; procedure A2: 0.150 mL if liquid or 1.1 eq when solid) was added and the reaction mixture was stirred overnight (procedure A1, A2 and A3), or 30 minutes (procedure A4) at room temperature.

Workup Procedure A1, A2 and A4: The mixture was washed with 1M HCl (5 mL) and the organic layer was loaded on a silica column and purified using gradient elution from heptane to EtOAc.

Workup Procedure A3: The organic layer was loaded on a silica column and purified using gradient elution from heptane to EtOAc.

#

Reagent A Synthetic Procedure LC-MS method Rt (min.) [M + NH₄]⁺ or [M + H]⁺ Exact mass  4

Methanesulfonyl chloride A1 C 0.80 318.1 300.1  5

Cyclopropanesulfonyl chloride A1 C 0.88 344.3 326.1  6

1-Propanesulfonyl chloride A1 C 0.93 346.2 328.1  7

Isopropylsulfonyl chloride A1 C 0.91 346.2 328.1  8

Cyclopropylmethane- sulfonyl chloride A1 C 0.93 358.2 340.1  9

Tetrahydro-2H-pyran-4- sulfonyl chloride A1 C 0.85 388.2 370.1 10

Cyclopentanesulfonyl chloride A1 C 0.99 372.1 354.1 11

N-Isopropyl-N-methyl- sulfamoyl chloride A2 C 1.00 358.2 357.2 12

Tetrahydro-3- furansulfonyl chloride A2 C 0.83 374.3 356.1 13

1,1-Dioxothiolane-3- sulfonyl chloride A2 C 0.82 422.2 404.1 14

2-Methoxy- ethanesulfonyl chloride A2 C 0.85 362.1 344.1 15

4-Hydroxy-1,1-dioxo- thiolane-3-sulfonyl chloride A2 C  0.76/ 0.77 438.2 420.1 16

2-Hydroxycyclohexane- sulfonyl chloride A2 C 0.90 402.2 384.2 17

4-Methylpentane-2- sulfonyl chloride A2 C 1.11 388.2 370.2 18

1-Methoxypropane-2- sulfonyl chloride A2 C 0.90 376.2 358.1 19

Pentane-3-sulfonyl chloride A2 C 1.05 374.2 356.2 20

(2,5-dioxopyrrolidin-1- yl) oxetan-3-yl carbonate A3 C 0.79 340.1 322.1 21

Isopropyl chloroformate A3 C 0.96 326.2 308.2 22

Methyl chloroformate A3 C 0.82 298.2 280.1 23

Cyclohexanesulfonyl chloride A4 C 1.05 386.2 368.2 24

2-Ethyl-cyclopropane- sulfonyl chloride A4 C 1.00 372.1 354.1 25

Sec-butylsulfonyl chloride A4 C 0.97 360.2 342.1 26

Isobutyl chloroformate A4 C 1.03 340.2 322.2

Compound 6: (3S)—N-(4-fluoro-3-methyl-phenyl)-1-propylsulfonyl-pyrrolidine-3-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00 (t, J=7.5 Hz, 3H), 1.66-1.77 (m, 2H), 2.01-2.12 (m, 1H), 2.12-2.19 (m, 1H), 2.20 (d, J=1.8 Hz, 3H), 3.04-3.11 (m, 2H), 3.17 (quin, J=7.4 Hz, 1H), 3.27-3.31 (m, 1H), 3.34-3.43 (m, 2H), 3.56 (dd, J=10.0, 7.8 Hz, 1H), 7.07 (t, J=9.2 Hz, 1H), 7.34-7.43 (m, 1H), 7.50 (dd, J=7.0, 2.4 Hz, 1H), 10.02 (s, 1H).

Compound 8: (3S)-1-(cyclopropylmethylsulfonyl)-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.31-0.39 (m, 2H), 0.55-0.64 (m, 2H), 0.97-1.10 (m, 1H), 2.01-2.12 (m, 1H), 2.12-2.19 (m, 1H), 2.20 (d, J=1.8 Hz, 3H), 3.07 (d, J=7.0 Hz, 2H), 3.18 (quin, J=7.6 Hz, 1H), 3.33-3.38 (m, 1H), 3.38-3.47 (m, 2H), 3.59 (dd, J=9.7, 7.9 Hz, 1H), 7.07 (t, J=9.2 Hz, 1H), 7.35-7.43 (m, 1H), 7.50 (dd, J=7.0, 2.2 Hz, 1H), 10.02 (s, 1H).

Compound 9: (3S)—N-(4-fluoro-3-methyl-phenyl)-1-tetrahydropyran-4-ylsulfonyl-pyrrolidine-3-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.59-1.75 (m, 2H), 1.81-1.94 (m, 2H), 2.02-2.19 (m, 2H), 2.20 (d, J=1.8 Hz, 3H), 3.18 (quin, J=7.4 Hz, 1H), 3.32-3.56 (m, 6H), 3.62 (dd, J=9.7, 7.9 Hz, 1H), 3.87-3.98 (m, 2H), 7.07 (t, J=9.1 Hz, 1H), 7.34-7.43 (m, 1H), 7.50 (dd, J=7.0, 2.4 Hz, 1H), 10.02 (s, 1H).

Compound 10: (3S)-1-cyclopentylsulfonyl-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.49-1.61 (m, 2H), 1.61-1.73 (m, 2H), 1.77-1.89 (m, 2H), 1.89-2.01 (m, 2H), 2.03-2.18 (m, 2H), 2.20 (d, J=1.8 Hz, 3H), 3.16 (quin, J=7.5 Hz, 1H), 3.33-3.46 (m, 3H), 3.60 (dd, J=9.7, 7.9 Hz, 1H), 3.71 (quin, J=8.1 Hz, 1H), 7.07 (t, J=9.2 Hz, 1H), 7.35-7.42 (m, 1H), 7.50 (dd, J=7.0, 2.4 Hz, 1H), 10.02 (s, 1H)

Compound 24: (3S)-1-(2-ethylcyclopropyl)sulfonyl-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81-0.90 (m, 1H), 0.92-0.98 (m, 3H), 1.05-1.13 (m, 1H), 1.28-1.42 (m, 3H), 2.01-2.19 (m, 2H), 2.19-2.23 (m, 3H), 2.52-2.54 (m, 1H), 3.13-3.24 (m, 1H), 3.33-3.38 (m, 1H), 3.38-3.48 (m, 2H), 3.54-3.63 (m, 1H), 7.07 (t, J=9.2 Hz, 1H), 7.36-7.43 (m, 1H), 7.48-7.54 (m, 1H), 10.02 (s, 1H).

The mixture 24 was separated in 2 isomers by Prep SFC (Stationary phase: Chiralcel Diacel OJ 20×250 mm), mobile phase: CO₂, iPrOH with 0.2% iPrNH₂). OJ-H 250 mm×4.6 mm, Flow: 5 mL/min, Mobile phase: 15% EtOH (containing 0.2% iPrNH₂) hold 4 min. Rt: 24a: 1.68 min, 24b: 2.04 min.

Compound 25: (3S)—N-(4-fluoro-3-methyl-phenyl)-1-sec-butylsulfonyl-pyrrolidine-3-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.96 (t, J=7.5 Hz, 3H) 1.22-1.26 (m, 3H) 1.36-1.54 (m, 1H) 1.81-1.97 (m, 1H) 2.02-2.18 (m, 2H) 2.20 (d, J=1.8 Hz, 3H) 3.09-3.26 (m, 2H) 3.33-3.48 (m, 3H) 3.57-3.66 (m, 1H) 7.06 (t, J=9.2 Hz, 1H) 7.33-7.43 (m, 1H) 7.51 (dd, J=7.0, 2.6 Hz, 1H) 10.02 (s, 1H)

Compound 26: isobutyl (3S)-3-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrolidine-1-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.89 (d, J=6.6 Hz, 6H), 1.80-1.92 (m, 1H), 1.94-2.18 (m, 2H), 2.18-2.24 (m, 3H), 3.04-3.21 (m, 1H), 3.24-3.38 (m, 1H), 3.35-3.50 (m, 2H), 3.50-3.63 (m, 1H), 3.77 (d, J=6.4 Hz, 2H), 7.06 (t, J=9.2 Hz, 1H), 7.35-7.42 (m, 1H), 7.49-7.52 (m, 1H), 10.00 (s, 1H).

Compound 27: (1S,5S)—N-(4-fluoro-3-methyl-phenyl)-3-isobutylsulfonyl-3-azabicyclo[3.1.0]hexane-1-carboxamide

Ethyl 3-benzyl-3-azabicyclo[3.1.0]hexane-5-carboxylate (1.03 g, 4.2 mmol) was dissolved in THF (40 mL). Water (10 mL) and LiOH (0.5 g, 20.9 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours and next refluxed for 24 hours. The reaction mixture was concentrated to dryness in vacuo, and residual water was removed by coevaporation with toluene (2×20 mL), resulting in a residue. The obtained residue was suspended in CH₂Cl₂ (50 mL, dry) and NEt₃.HCl (5.8 g, 42.0 mmol), 4-fluoro-3-methyl-aniline (0.79 g) and HATU (4.8 g, 12.6 mmol) were added successively. The reaction mixture was stirred at room temperature for 2 hours. DMF (100 mL) and more 4-fluoro-3-methyl-aniline (0.53 g) was added to the reaction mixture. The reaction mixture was further stirred at room temperature over weekend. The reaction mixture was diluted with CH₂Cl₂ (100 mL), washed with saturated aqueous sodium bicarbonate (2×50 mL), dried (Na₂SO₄), and concentrated in vacuo resulting in a residue. The obtained residue was purified using silica gel column chromatography by gradient elution with ethyl acetate in heptane from 0 to 100% and next ethylacetate in heptane from 20 to 25% resulting in 3-benzyl-N-(4-fluoro-3-methyl-phenyl)-3-azabicyclo[3.1.0]hexane-5-carboxamide (400 mg). Method C; Rt: 1.17 min. m/z: 325.2 (M+H)⁺ Exact mass: 324.2. 3-benzyl-N-(4-fluoro-3-methyl-phenyl)-3-azabicyclo[3.1.0]hexane-5-carboxamide (400 mg) was dissolved in methanol (50 mL) and Pd/C 10% (262 mg) was added. The solution was stirred under H₂ atmosphere for 1 hour at room temperature. After filtration on dicalite, the mixture was concentrated in vacuo, resulting in N-(4-fluoro-3-methyl-phenyl)-3-azabicyclo[3.1.0]hexane-5-carboxamide (282 mg). Method C; Rt: 0.60 min. m/z: 235.2 (M+H)⁺ Exact mass: 234.1. To a solution of N-(4-fluoro-3-methyl-phenyl)-3-azabicyclo[3.1.0]hexane-5-carboxamide (142 mg, 0.606 mmol) in CH₂Cl₂ (5 mL) was added DIPEA (0.84 mL, 4.85 mmol) and 2-methylpropane-1-sulfonyl chloride (142.4 mg, 0.91 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then diluted with CH₂Cl₂ (10 mL), washed with aqueous HCl (1 N, 10 mL), brine and dried (Na₂SO₄). After removal of the volatiles in vacuo, the obtained residue was purified using silica gel column chromatography (ethyl acetate in heptane from 20-30%) resulting in a sticky residue. This residue was triturated in diisopropylether and the obtained white solid was filtered, washed with petroleum ether and dried in vacuo, resulting in compound 27 (124 mg) as a white powder. Method C; Rt: 1.02 min. m/z: 372.2 (M+NH₄)⁺ Exact mass: 354.1. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.11 (d, J=6.8 Hz, 6H), 1.17 (t, J=5.2 Hz, 1H), 1.52 (dd, J=8.4, 5.3 Hz, 1H), 2.17 (ddd, J=8.4, 5.0, 3.9 Hz, 1H), 2.21-2.33 (m, 4H), 2.87 (d, J=6.6 Hz, 2H), 3.48 (dd, J=9.7, 3.7 Hz, 1H), 3.62 (d, J=9.5 Hz, 1H), 3.74 (d, J=9.0 Hz, 1H), 3.82 (d, J=8.8 Hz, 1H), 6.95 (t, J=8.9 Hz, 1H), 7.03 (br. s, 1H), 7.17-7.24 (m, 1H), 7.34 (dd, J=6.6, 2.6 Hz, 1H).

Compound 28: N-(4-fluoro-3-methyl-phenyl)-1-isobutylsulfonyl-indoline-3-carboxamide

Indoline-3-carboxylic acid (1 g, 6.13 mmol) was dissolved in DMF (10 mL) and water (5 mL) was added. After addition of DIPEA (2.4 mL, 14.1 mmol), the reaction mixture was stirred for 10 minutes. Then, 2-methylpropane-1-sulfonyl chloride (0.96 g, 6.128 mmol) was added dropwise and the reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned between CH₂Cl₂ and water set to pH=10 with 1M NaOH. The organic layer was removed and the aqueous layer was acidified with conc. HCl to pH=1. The product was extracted with CH₂Cl₂. The organic layer was dried with MgSO₄, filtered and concentrated to dryness in vacuo, yielding 1-isobutylsulfonylindoline-3-carboxylic acid as an oil (600 mg), which was used as such in the next step. 1-isobutylsulfonylindoline-3-carboxylic acid (600 mg), 4-fluoro-3-methylaniline (265 mg, 2.12 mmol) and DIPEA (1.1 mL, 6.35 mmol) were dissolved in CH₂Cl₂ (20 mL). HATU (966.2 mg, 2.54 mmol) was added and the resulting mixture was stirred overnight at room temperature. The reaction mixture was washed with 1M HCl (15 mL) and the organic layer was evaporated to dryness. The obtained residue was purified by silica gel column chromatography using a heptane to EtOAc gradient yielding compound 28 (36.2 mg) as an off-white powder. Method E; Rt: 2.03 min. m/z: 391.0 (M+H)⁺ Exact mass: 390.1. ¹H NMR (400 MHz, DMSO-d₆) ppm 1.04 (d, J=6.8 Hz, 3H), 1.03 (d, J=6.6 Hz, 3H), 2.11-2.19 (m, 1H), 2.21 (d, J=1.3 Hz, 3H), 3.00-3.17 (m, 2H), 4.14-4.22 (m, 1H), 4.23-4.31 (m, 1H), 4.31-4.38 (m, 1H), 7.01-7.13 (m, 2H), 7.23-7.34 (m, 2H), 7.38-7.48 (m, 2H), 7.52 (dd, J=7.0, 2.4 Hz, 1H), 10.42 (s, 1H)

Compound 29: N-(4-fluoro-3-methyl-phenyl)-1-isobutylsulfonyl-3-methyl-pyrrolidine-3-carboxamide

Synthesised similarly as described for compound 28, using 3-methyl-pyrrolidine-3-carboxylic acid instead of indoline-3-carboxylic acid Method C; Rt: 1.04 min. m/z: 374.3 (M+NH₄)⁺ Exact mass: 356.2. ¹H NMR (400 MHz, DMSO-d₆) ppm 0.97-1.03 (m, 6H), 1.39 (s, 3H), 1.81-1.92 (m, 1H), 2.03-2.15 (m, 1H), 2.21 (d, J=1.8 Hz, 3H), 2.38-2.47 (m, 1H), 2.93 (d, J=6.6 Hz, 2H), 3.20 (d, J=9.9 Hz, 1H), 3.23-3.30 (m, 1H), 3.33-3.41 (m, 1H), 3.75 (d, J=9.9 Hz, 1H), 7.07 (t, J=9.1 Hz, 1H), 7.38-7.47 (m, 1H), 7.52 (dd, J=7.0, 2.4 Hz, 1H), 9.56 (s, 1H). The racemic mixture 29 was separated in enantiomers 29a and 29b by preparative SFC (Stationary phase: Chiralpak Diacel AS 20×250 mm), Mobile phase: CO₂, MeOH with 0.4% iPrNH₂). AS-H 250 mm×4.6 mm, Flow: 5 mL/min, Mobile phase: 20% MeOH (containing 0.2% iPrNH₂) hold 7 min. Rt: 29a: 1.36 min, 29b: 1.72 min.

Compound 30: N-(4-fluoro-3-methyl-phenyl)-7-isobutylsulfonyl-7-azabicyclo[2.2.1]heptane-3-carboxamide (racemic mixture, diastereomeric pure)

4-fluoro-3-methylaniline (0.622 g, 4.97 mmol) was dissolved in CH₂Cl₂ (60 mL). Then (+/−)-7-tert-butoxycarbonyl-7-azabicyclo[2.2.1]heptane-3-carboxylic acid (1 g, 4.14 mmol) was added followed by DIPEA (2.14 mL, 12.4 mmol) and this mixture was stirred for 10 minutes. Then, HATU (2.36 g, 6.12 mmol) was added portion wise. The resulting mixture was stirred for 1.5 hours. Then, NaOH (1M in H₂O, 16.6 mL) was added. The resulting mixture was extracted with CH₂Cl₂ (3×25 mL) and the combined organics were dried (MgSO₄), filtered and concentrated in vacuo. The obtained crude was purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0:100 to 30:70), resulting in tert-butyl 3-[(4-fluoro-3-methyl-phenyl)-carbamoyl]-7-azabicyclo[2.2.1]heptane-7-carboxylate (77 mg). Tert-butyl 3-[(4-fluoro-3-methyl-phenyl)carbamoyl]-7-azabicyclo[2.2.1]heptane-7-carboxylate (77 mg) was dissolved in 1,4-dioxane (2 mL) and HCl (4 M in dioxane, 0.88 mL) was added in 3 portions over 1 hour. 30 minutes after the last addition, the mixture was concentrated at 50° C. under a gentle flow of nitrogen. The obtained crude was used as such. Method C; Rt: 0.58 min. m/z: 249.2 (M+H)⁺ Exact mass: 248.1. The above obtained crude was stirred in CH₂Cl₂ (2 mL) and DIPEA (0.30 mL, 1.8 mmol) was added, followed by 2-methylpropane-1-sulfonyl chloride (43 μL, 0.331 mL). The reaction mixture was stirred overnight. The reaction mixture was poured into dichloromethane (5 mL) and treated with HCl (1M in H₂O, 2.2 mL). The layers were separated and the organics were dried on MgSO₄, filtered and concentrated in vacuo. The obtained crude was chromatographed using silica gel column chromatography (gradient elution: EtOAc-heptane 0:100 to 20:80). The combined fractions were concentrated and the obtained residue was dried in vacuo, resulting in compound 30 (32.1 mg). Method C; Rt: 1.04 min. m/z: 386.3 (M+NH₄)+ Exact mass: 368.2. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.10 (d, J=6.5 Hz, 6H), 1.56-1.64 (m, 2H), 1.92 (dd, J=12.3, 9.5 Hz, 1H), 2.01-2.14 (m, 2H), 2.14-2.20 (m, 1H), 2.25 (d, J=2.0 Hz, 3H), 2.33 (spt, J=6.7 Hz, 1H), 2.60 (dd, J=9.1, 5.0 Hz, 1H), 2.92-3.05 (m, 2H), 4.31 (t, J=4.4 Hz, 1H), 4.47 (d, J=4.4 Hz, 1H), 6.93 (t, J=8.9 Hz, 1H), 7.21-7.30 (m, 1H), 7.35 (dd, J=6.9, 2.4 Hz, 1H), 7.76 (br. s., 1H).

Compound 31: (3S)—N-(4-fluoro-3-methyl-phenyl)-1-(isobutylsulfamoyl)pyrrolidine-3-carboxamide

(3S)—N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide hydrochloride (50 mg, 0.193 mmol) and NH₂SO₂NH₂ (93 mg, 0.966 mmol) were suspensed in dioxane (3 mL) in a sealed microwave tube The tube was heated overnight at 100° C. The reaction mixture was used as such in the next reaction. To the above reaction mixture, isobutylamine was added (1 mL). The tube was heated overnight at 100° C. The reaction mixture was evaporated to dryness and purified on silica using a heptane to EtOAc gradient, followed by preparative HPLC (RP Vydac Denali C18-10 μm, 250 g, 5 cm). Mobile phase (0.25% NH₄HCO₃ solution in water, MeOH), the desired fractions were collected, evaporated, dissolved in MeOH and evaporated again, resulting in compound 31 (3.5 mg). Method C; Rt: 0.98 min. m/z: 375.2 (M+NH₄)⁺ Exact mass: 357.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.86 (d, J=6.8 Hz, 6H), 1.62-1.74 (m, 1H), 1.99-2.18 (m, 2H), 2.20 (d, J=1.8 Hz, 3H), 2.73 (d, J=6.8 Hz, 2H), 3.09-3.30 (m, 4H), 3.47 (dd, J=9.5, 8.1 Hz, 1H), 7.06 (t, J=9.1 Hz, 1H), 7.17 (br. s., 1H), 7.35-7.44 (m, 1H), 7.51 (dd, J=7.2, 2.3 Hz, 1H), 10.02 (br. s., 1H).

Compound 32: (3S)—N-(4-fluoro-3-methyl-phenyl)-1-(isopropylsulfamoyl)pyrrolidine-3-carboxamide

Catechol (10 g, 90.8 mmol) and pyridine (14.6 mL, 181.6 mmol) dissolved in heptane (60 mL) were stirred at −5° C. Sulfuryl chloride (12.26 g, 90.8 mmol) dissolved in heptanes (20 mL) was added dropwise while maintaining the temperature at −5° C. After complete addition, the reaction mixture was stirred for 2 hours at −5° C. The reaction mixture was allowed to reach room temperature and was used as such in the next step. Isopropylamine (7.7 mL, 90.8 mmol) and then NEt₃ (12.6 mL, 90.8 mmol) where added to the above obtained reaction mixture at room temperature. The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was poured in a CH₂Cl₂/water mixture. The organic layer was separated and evaporated to dryness. The obtained residue was purified by silica gel column chromatography applying gradient elution from heptane to EtOAc. The product fractions were collected and evaporated to dryness yielding (2-hydroxyphenyl)N-isopropylsulfamate (3.28 g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.14 (d, J=6.6 Hz, 6H), 3.56-3.68 (m, 1H), 6.77-6.83 (m, 1H), 6.95 (dd, J=8.0, 1.7 Hz, 1H), 7.05-7.12 (m, 1H), 7.25 (dd, J=8.1, 1.8 Hz, 1H), 8.05 (d, J=7.0 Hz, 1H), 9.75 (s, 1H). (3S)—N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide hydrochloride, (2-hydroxyphenyl)N-isopropylsulfamate (300 mg, 1.30 mmol) and NEt₃ (0.134 mL, 0.966 mmol) were dissolved in CH₃CN (3 mL) and heated in the microwave for 10 minutes at 100° C. The tube was heated again for 15 minutes at 100° C. More NEt₃ (0.1 mL) was added and the tube was heated again for 30 minutes. The volatiles were removed under reduced pressure and the residue was purified by silica gel column chromatography using a heptane to EtOAc gradient, followed by prep. HPLC. (RP Vydac Denali C18-10 μm, 250 g, 5 cm). Mobile phase (0.25% NH₄HCO₃ solution in water, MeOH), the desired fractions were collected, evaporated, dissolved in MeOH and evaporated again, the obtained residue was crystallized from CH₃CN/diisopropylether, resulting in compound 32 (95.8 mg). Method C; Rt: 0.91 min. m/z: 344.2 (M+H)⁺ Exact mass: 343.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09-1.13 (m, 6H), 1.98-2.18 (m, 2H), 2.20 (d, J=1.8 Hz, 3H), 3.09-3.29 (m, 4H), 3.34-3.50 (m, 2H), 7.02-7.11 (m, 2H), 7.34-7.42 (m, 1H), 7.50 (dd, J=7.0, 2.4 Hz, 1H), 10.00 (s, 1H); Differential scanning calorimetry (From 30 to 300° C. at 10° C./min), Peak: 101.1° C. [α]_(D) ²⁰: −6.2° (c 0.54 w/v %, DMF)

Compound 33: (3S)—N-(4-fluoro-3-methyl-phenyl)-1-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]pyrrolidine-3-carboxamide

(S)-(−)-3-aminotetrahydrofuran p-toluenesulfonate (301.3 mg, 1.16 mmol) was added to a stirred mixture of 1,3,2-Benzodioxathiole 2,2-dioxide (200 mg, 1.16 mmol) and NEt₃ (484 μL, 3.49 mmol) in 1,4-dioxane (10 mL). (3S)—N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide hydrochloride (258 mg) was added to the reaction mixture. The mixture was heated at 100° C. for 10 minutes, cooled to room temperature, heated at 100° C. for 30 minutes more and cooled to room temperature. The reaction mixture was stored at room temperature over weekend. The mixture was filtered, the filtrate was concentrated and the obtained residue was diluted with CH₂Cl₂ (10 mL). The organic layer was washed with aqueous hydrochloric acid (1N, 2×10 mL), dried (Na₂SO₄) and evaporated to dryness. The residue was purified using silica gel column chromatography by gradient elution with ethyl acetate in heptanes, resulting in compound 33 (51 mg). Method C; Rt: 0.80 min. m/z: 372.2 (M+H)⁺ Exact mass: 371.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.75-1.88 (m, 1H), 1.98-2.18 (m, 3H), 2.20 (d, J=1.8 Hz, 3H), 3.10-3.35 (m, 4H), 3.41-3.54 (m, 2H), 3.65 (td, J=8.0, 5.9 Hz, 1H), 3.70-3.81 (m, 2H), 3.82-3.92 (m, 1H), 7.06 (t, J=9.1 Hz, 1H), 7.35-7.43 (m, 1H), 7.46 (br. s, 1H), 7.51 (dd, J=7.0, 2.2 Hz, 1H), 10.02 (br. s, 1H). [α]_(D) ²⁰ : −6.4° (c 0.63 w/v %, DMF).

Compound 34: (3S)—N-(4-fluoro-3-methyl-phenyl)-1-[(3-methyloxetan-3-yl)sulfamoyl]pyrrolidine-3-carboxamide

2,3-Dimethyl-1-[(2-methyl-1H-imidazol-1-yl)sulfonyl]-1H-imidazol-3-ium trifluoromethanesulfonate (1.51 g, 3.87 mmol), (3S)—N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide hydrochloride (500 mg, 1.93 mmol) and DIPEA (1.67 mL, 9.66 mmol) were dissolved in CH₃CN (5 mL) and stirred for 30 minutes at room temperature. The volatiles were removed under reduced pressure and the obtained residue was purified by silica gel column chromatography from heptane to EtOAc gradient resulting in (3S)—N-(4-fluoro-3-methyl-phenyl)-1-(2-methylimidazol-1-yl)sulfonyl-pyrrolidine-3-carboxamide (387 mg). (3S)—N-(4-fluoro-3-methyl-phenyl)-1-(2-methylimidazol-1-yl)sulfonyl-pyrrolidine-3-carboxamide (387 mg, 1.056 mmol) was dissolved in CH₂Cl₂ (10 mL) and the mixture was cooled with an ice bath. Methyl trifluoromethanesulfonate (190.7 mg, 1.16 mmol) was added and the reaction mixture was stirred for 2 hours at 0° C. The volatiles were removed under reduced pressure and the obtained residue was dissolved in CH₃CN (10 mL), together with 3-methyl-3-oxetanamine hydrochloride (1:1) (163.1 mg, 1.32 mmol) and DIPEA (0.364 mL, 2.11 mmol). The mixture was heated 1 hour at 80° C. The volatiles were removed under reduced pressure and the obtained residue was purified by silica gel column chromatography from heptanes to EtOAc gradient resulting in compound 34 (244 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.60 (s, 3H), 2.00-2.19 (m, 2H), 2.20 (d, J=1.8 Hz, 3H), 3.11-3.30 (m, 4H), 3.49 (dd, J=9.6, 8.3 Hz, 1H), 4.21 (d, J=6.3 Hz, 2H), 4.65 (d, J=6.3 Hz, 2H), 7.06 (t, J=9.2 Hz, 1H), 7.34-7.43 (m, 1H), 7.51 (dd, J=7.0, 2.4 Hz, 1H), 7.62 (s, 1H), 10.02 (s, 1H). Method C; Rt: 0.81 min. m/z: 389.2 (M+NH₄)⁺ Exact mass: 371.1.

Compound 35: 3-fluoro-N-(4-fluoro-3-methyl-phenyl)-1-(isopropylsulfamoyl)pyrrolidine-3-carboxamide

To a solution of 1-benzyl-3-fluoro-pyrrolidine-3-carboxylic acid (3.06 g, 13.7 mmol) (synthesis described in Tetrahedron Letters (2011), 52(12), 1300-1302) in DMF (30 mL) was added triethylamine hydrochloride (9.43 g, 68.5 mmol), triethylamine (5.71 mL, 41.1 mmol), HATU (4.83 g, 20.6 mmol) and 4-fluoro-3-methyl-aniline (1.71 g, 13.7 mmol). The reaction mixture was stirred at room temperature for 1 hour and diluted with water (200 mL). The solids were filtered and washed with water to afford 1-benzyl-3-fluoro-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide as a light purple powder (2.65 g). A second crop (120 mg) was isolated from the filtrate. Both powders were combined for the next step. 1-benzyl-3-fluoro-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide (2.77 g, 8.37 mmol) was dissolved in MeOH (150 mL) and 10% Pd on charcoal (0.89 g) was added. This mixture was hydrogenated at room temperature at a H₂ pressure of 1 atm for 30 minutes. The solids were filtered off and the filtrate was evaporated under reduced pressure to afford 3-fluoro-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide (1.21 g) as an off white solid. Method E; Rt: 1.23 min. m/z: 241.4 (M+H)⁺ Exact mass: 240.1.

3-fluoro-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide (250 mg, 0.98 mmol), (2-hydroxyphenyl)N-isopropylsulfamate (294 mg, 1.27 mmol) and triethylamine (0.27 mL, 1.96 mmol) were dissolved in ACN (3 mL) and heated in the microwave for 10 minutes at 100° C.

The volatiles were removed under reduced pressure. The residue was dissolved in DCM (20 mL) and washed with aqueous HCl (1 N) (2×5 mL) and brine (5 mL). The organic layer was concentrated to dryness and the residue was purified by silica gel chromatography by gradient elution with ethyl acetate in heptanes yielding a sticky oil. This was dissolved in methanol (2 mL). To this solution was added water (8 mL). The suspension was heated at reflux and the emulsion became suspension overnight. The solids were filtered and washed with methanol in water (20%, 2×2 mL) to afford compound 35 as a white solid which was dried in vacuum oven over weekend at 50° C. (210 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.13 (dd, J=6.5, 0.8 Hz, 6H), 2.21 (d, J=1.8 Hz, 3H), 2.27-2.41 (m, 1H), 2.41-2.61 (m, 1H), 3.34-3.52 (m, 3H), 3.53-3.73 (m, 2H), 7.10 (t, J=9.2 Hz, 1H), 7.26 (br. d, J=7.3 Hz, 1H), 7.50 (ddd, J=8.7, 4.7, 2.9 Hz, 1H), 7.63 (dd, J=7.0, 2.2 Hz, 1H), 10.21 (br. s., 1H). Method C; Rt: 0.96 min. m/z: 379.2 (M+NH₄)⁺ Exact mass: 361.1.

The racemic mixture 35 was separated in enantiomers by Prep SFC (Stationary phase: Chiralcel Diacel OD 20×250 mm), mobile phase: CO₂, iPrOH with 0.4% iPrNH₂). OD-H 250 mm×4.6 mm, Flow: 5 mL/min, Mobile phase: 35% MeOH (containing 0.2% iPrNH₂) hold 4 min. Rt: 35a: 2.39 min, 35b: 2.87 min.

Compound 36: N-(4-fluoro-3-methyl-phenyl)-2-(isopropylsulfamoyl)-2-azabicyclo[3.1.0]hexane-4-carboxamide

To a solution of 2-tert-butoxycarbonyl-2-azabicyclo[3.1.0]hexane-4-carboxylic acid (1000 mg, 4.4 mmol) in DMF (10 mL) was added triethylamine (1.83 mL, 13.2 mmol), HATU (2.51 g, 6.60 mmol) followed by 4-fluoro-3-methyl-aniline (716 mg, 5.72 mmol). The reaction mixture was stirred at room temperature for 1 hour and diluted with water (100 mL). The solids were filtered and washed with water to afford tert-butyl 4-[(4-fluoro-3-methyl-phenyl)carbamoyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate as a brown sticky solid. This was redissolved in DCM, dried over MgSO4, filtered and used as such in the next step. Method C; Rt: 1.02 min and 1.05 min. m/z: 335.2 (M+H)⁺ Exact mass: 334.2.

To a solution of tert-butyl 4-[(4-fluoro-3-methyl-phenyl)carbamoyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate (1.47 g, 4.4 mmol) in DCM (200 mL) was added TFA (6.73 mL, 88 mmol). The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was evaporated to dryness to afford N-(4-fluoro-3-methyl-phenyl)-2-azabicyclo[3.1.0]hexane-4-carboxamide as a brown oil. Method C; Rt: 0.58 min and 0.60 min. m/z: 235.2 (M+H)⁺ Exact mass: 234.1.

N-(4-fluoro-3-methyl-phenyl)-2-azabicyclo[3.1.0]hexane-4-carboxamide (300 mg, 0.86 mmol), (2-hydroxyphenyl)N-isopropylsulfamate (259 mg, 1.12 mmol) and triethylamine (0.36 mL, 2.58 mmol) were dissolved in ACN (5 mL) and heated in the microwave for 10 minutes at 100° C.

The volatiles were removed under reduced pressure and the residue was dissolved in DCM (20 mL), washed with aqueous HCl (1 M) (2×5 mL) and brine (5 mL). The organic layer was concentrated to dryness and the residue was purified using silica gel chromatography using a ethyl acetate in heptane gradient (from 20 to 100%) yielding compound 36a (TRANS-isomer) as a white powder (36 mg) ¹H NMR (600 MHz, DMSO-d₆) δ ppm 0.62 (dt, J=8.7, 5.9 Hz, 1H), 0.94 (ddd, J=6.0, 4.7, 2.6 Hz, 1H), 1.12 (dd, J=6.6, 1.6 Hz, 6H), 1.78 (ddd, J=8.8, 6.0, 6 4.8 Hz, 1H), 2.20 (d, J=1.8 Hz, 3H), 2.95 (dd, J=10.5, 7.8 Hz, 1H), 3.12 (td, J=5.9, 2.7 Hz, 1H), 3.22 (dd, J=7.8, 1.1 Hz, 1H), 3.43 (q, J=6.5 Hz, 1H), 3.47 (d, J=10.4 Hz, 1H), 7.07 (t, J=9.2 Hz, 1H), 7.15 (br. s., 1H), 7.38-7.41 (m, 1H), 7.51 (dd, J=7.0, 2.2 Hz, 1H), 9.99 (s, 1H). Method C; Rt: 0.90 min. m/z: 356.1 (M+H)⁺ Exact mass: 355.1. and impure compound 36b as a colorless oil. This was further purified using prep. LCMS. (Hypersyl C18 BDS-3 μm, 100×4.6 mm) Mobile phase (NH₄HCO₃ 0.2% in water, acetonitrile). The desired fractions were combined and evaporated to dryness, dissolved in methanol again and evaporated to dryness and dried in a vacuum oven overnight to yield compound 36b (CIS-isomer) (40 mg). ¹H NMR (600 MHz, DMSO-d₆) δ ppm 0.50 (dt, J=8.4, 6.1 Hz, 1H), 1.11 (ddd, J=6.3, 4.4, 2.9 Hz, 1H), 1.14 (dd, J=6.6, 2.9 Hz, 6H), 1.85-1.96 (m, 1H), 6 2.21 (d, J=1.8 Hz, 3H), 3.06-3.13 (m, 1H), 3.16 (td, J=6.1, 2.7 Hz, 1H), 3.28-3.31 (m, 1H), 3.33-3.35 (m, 1H), 3.39 (s, 1H), 3.41-3.50 (m, 1H), 7.07 (t, J=9.2 Hz, 1H), 7.21 (br. s., 1H), 7.39 (ddd, J=8.5, 4.6, 2.8 Hz, 1H), 7.53 (dd, J=7.1, 2.3 Hz, 1H), 10.07 (s, 1H). Method C; Rt: 0.92 min. m/z: 356.1 (M+H)⁺ Exact mass: 355.1

Compound 37: (3S)—N-(4-fluoro-3-methyl-phenyl)-1-[[(1R,2R)-2-hydroxyindan-1-yl]sulfamoyl]pyrrolidine-3-carboxamide

Compound 37 was prepared similarly as compound 34, using (1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol instead of 3-methyl-3-oxetanamine hydrochloride (1:1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.05-2.18 (m, 2H), 2.20 (s, 3H), 2.67 (dd, J=15.5, 6.9 Hz, 1H), 3.06-3.25 (m, 2H), 3.33-3.43 (m, 3H), 3.61 (t, J=8.8 Hz, 1H), 4.22 (quin, J=6.4 Hz, 1H), 4.49 (t, J=7.0 Hz, 1H), 5.30 (d, J=5.7 Hz, 1H), 7.07 (t, J=9.2 Hz, 1H), 7.14-7.29 (m, 3H), 7.32-7.45 (m, 2H), 7.52 (dd, J=6.9, 2.3 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 10.01 (s, 1H). Method C; Rt: 0.91 min. m/z: 434.2 (M+H)⁺ Exact mass: 433.1.

Compound 38: tert-butyl N-[2-[[(3S)-3-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrolidin-1-yl]sulfonylamino]propyl]carbamate

Compound 38 was prepared similarly as compound 34, using carbamic acid, N-(2-aminopropyl)-, 1,1-dimethylethyl ester instead of 3-methyl-3-oxetanamine hydrochloride (1:1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05 (d, J=6.6 Hz, 3H), 1.37 (s, 9H), 1.97-2.17 (m, 2H), 2.17-2.23 (m, 3H), 2.88 (dt, J=13.4, 6.5 Hz, 1H), 2.96-3.08 (m, 1H), 3.09-3.29 (m, 5H), 3.42-3.51 (m, 1H), 6.79 (br. s., 1H), 7.00-7.11 (m, 2H), 7.34-7.42 (m, 1H), 7.50 (dd, J=6.9, 2.1 Hz, 1H), 9.99 (s, 1H). Method C; Rt: 0.99 min. m/z: 459.2 (M+H)⁺ Exact mass: 458.2.

Compound 39: (3S)—N-(4-fluoro-3-methyl-phenyl)-1-[[(1R)-2-hydroxy-1-methyl-ethyl]sulfamoyl]pyrrolidine-3-carboxamide

Compound 39 was prepared similarly as compound 34, using D-alaninol instead of 3-methyl-3-oxetanamine hydrochloride (1:1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.10 (d, J=6.4 Hz, 3H), 1.98-2.18 (m, 2H), 2.20 (d, J=1.8 Hz, 3H), 3.09-3.31 (m, 6H), 3.39-3.53 (m, 2H), 4.70 (t, J=5.6 Hz, 1H), 6.98 (d, J=5.7 Hz, 1H), 7.06 (t, J=9.2 Hz, 1H), 7.34-7.44 (m, 1H), 7.51 (dd, J=7.0, 2.4 Hz, 1H), 10.00 (s, 1H). Method C; Rt: 0.75 min. m/z: 360.2 (M+H)⁺ Exact mass: 359.1.

Compound 40: (3S)-1-[(2-cyano-1-methyl-ethyl)sulfamoyl]-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide

Compound 40 was prepared similarly as compound 34, using 3-aminobutanenitrile instead of 3-methyl-3-oxetanamine hydrochloride (1:1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.23 (dd, J=6.7, 2.1 Hz, 3H), 2.00-2.12 (m, 1H), 2.12-2.19 (m, 1H), 2.20 (d, J=1.5 Hz, 3H), 2.60-2.79 (m, 2H), 3.11-3.22 (m, 1H), 3.22-3.28 (m, 1H), 3.28-3.38 (m, 2H), 3.45-3.54 (m, 1H), 3.54-3.66 (m, 1H), 7.06 (t, J=9.1 Hz, 1H), 7.36-7.43 (m, 1H), 7.51 (dd, J=7.0, 2.2 Hz, 1H), 7.62 (br. s, 1H), 10.02 (s, 1H). Method C; Rt: 0.83 min. m/z: 386.3 (M+NH₄)⁺ Exact mass: 368.1.

Compound 41: trans-N-(4-fluoro-3-methyl-phenyl)-1-(isopropylsulfamoyl)-4-methyl-pyrrolidine-3-carboxamide

Methyl crotonate (3.7 g, 15.6 mmol) is dissolved in DCM (50 ml) and combined with TFA (200 μl, 0.79 mmol). Then a solution of N-methoxymethyl-N-trimethylsilylmethyl-benzylamine (1.56 g, 15.6 mmol) in DCM (10 ml) is added drop wise within 20 minutes. The reaction mixture was stirred for 16 and then concentrated in vacuum. The residue was used as such in the next step. The crude mentioned above was dissolved in THF (40 mL) and combined with a solution of lithium hydroxide (3.74 g, 156 mmol) in water (10 mL). The mixture was stirred for 24 hours at room temperature. The reaction mixture was evaporated to dryness and water was removed with toluene (2×50 mL). The residue was used as such in the next step.

The crude mentioned above was dissolved in DMF (30 mL). Triethylamine hydrochloride (25.77 g, 187 mmol), triethylamine (6.51 mL, 46.8 mmol) and HATU were added followed by 4-fluoro-3-methyl-aniline (2.54 g, 20.3 mmol). The reaction mixture was stirred at RT for 1 hour. The reaction mixture was filtered under nitrogen atmosphere and diluted with water (200 mL). The solids were filtered and washed with water to afford a brown sticky solid. The organics in the filtrate were extracted with diethyl ether. The combined organic layers were combined with the brown sticky solid and washed with brine and evaporated to dryness. The residue was purified using silica gel column chromatography (ethyl acetate in heptane from 0 to 100%) to afford (3S,4S)-1-benzyl-N-(4-fluoro-3-methyl-phenyl)-4-methyl-pyrrolidine-3-carboxamide as a brown oil (1400 mg). Method C; Rt: 1.06 min. m/z: 327.2 (M+H)⁺ Exact mass: 326.1. This was used as such in the next step.

(3S,4S)-1-benzyl-N-(4-fluoro-3-methyl-phenyl)-4-methyl-pyrrolidine-3-carboxamide (1.40 g, 2.83 mmol) was dissolved in MeOH (50 mL) and 10% Pd on charcoal (3.01 g) was added. This mixture was hydrogenated at room temperature at a H₂ pressure of 1 atm for 90 minutes. The solids were filtered off and the filtrate was evaporated under reduced pressure to afford (3S,4S)—N-(4-fluoro-3-methyl-phenyl)-4-methyl-pyrrolidine-3-carboxamide (547 mg) as a colorless oil (547 mg).

(3S,4S)—N-(4-fluoro-3-methyl-phenyl)-4-methyl-pyrrolidine-3-carboxamide (274 mg, 1.16 mmol), (2-hydroxyphenyl)N-isopropylsulfamate (349 mg, 1.51 mmol) and triethylamine (0.48 mL, 3.48 mmol) were dissolved in ACN (3 mL) and heated in the microwave for 10 minutes at 100° C. The volatiles were removed under reduced pressure and the residue was purified using prep. LCMS. (Hypersyl C18 BDS-3 μm, 100×4.6 mm), mobile phase (NH₄HCO₃ 0.2% in water, methanol). The desired fractions were combined and evaporated to dryness, dissolved in methanol again and evaporated to dryness to afford a crude which was repurified using prep. LCMS. (Hypersyl C18 BDS-3 μm, 100×4.6 mm), mobile phase (NH₄HCO₃ 0.2% in water, acetonitrile). The desired fractions were combined and evaporated to dryness, dissolved in methanol again and evaporated to dryness and dried in a vacuum oven overnight to afford compound 41 (TRANS-isomer). ¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.04 (d, J=6.6 Hz, 3H), 1.12 (dd, J=6.5, 2.1 Hz, 6H), 2.20 (d, J=1.8 Hz, 3H), 2.41-2.48 (m, 1H), 2.71 (q, J=9.1 Hz, 1H), 2.80 (t, J=9.4 Hz, 1H), 3.25 (t, J=9.4 Hz, 1H), 3.39 (sxt, J=6.3 Hz, 1H), 3.45 (dd, J=9.5, 7.5 Hz, 1H), 3.52 (dd, J=9.7, 8.2 Hz, 1H), 7.07 (t, J=9.2 Hz, 2H), 7.40 (ddd, J=8.6, 4.5, 2.8 Hz, 1H), 7.53 (dd, J=7.0, 2.2 Hz, 1H), 10.05 (s, 1H). Method E; Rt: 1.73 min. m/z: 358.4 (M+H)⁺ Exact mass: 357.1.

Compound 42: 3-fluoro-N-(4-fluoro-3-methyl-phenyl)-1-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]pyrrolidine-3-carboxamide

(S)-(−)-3-aminotetrahydrofuran p-toluenesulfonate (5.0 g, 19.3 mmol) was added to a stirred mixture of 1,3,2-benzodioxathiole 2,2-dioxide (4.26 g, 19.3 mmol) and triethylamine (5.36 mL, 38.6 mmol) in ACN (50 mL). The reaction mixture was stirred for 18 hours. The reaction mixture was evaporated to dryness at 25° C. to afford a residue which was purified using silica gel column chromatography (ethyl acetate in heptane from 20 to 60%) to afford (2-hydroxyphenyl) N-[(3S)-tetrahydrofuran-3-yl]sulfamate as a slightly green sticky oil (2.4 g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.77-1.93 (m, 1H), 2.02-2.20 (m, 1H), 3.57 (dd, J=9.1, 4.1 Hz, 1H), 3.66 (td, J=8.2, 5.6 Hz, 1H), 3.70-3.80 (m, 2H), 4.02-4.23 (m, 1H), 6.78-6.84 (m, 1H), 6.96 (dd, J=8.1, 1.5 Hz, 1H), 7.07-7.15 (m, 1H), 7.23 (dd, J=7.9, 1.5 Hz, 1H), 8.46 (d, J=5.5 Hz, 1H), 9.85 (s, 1H).

3-fluoro-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide (400 mg, 1.57 mmol), (2-hydroxyphenyl)N-[(3S)-tetrahydrofuran-3-yl]sulfamate (487 mg, 1.88 mmol) and triethylamine (0.44 mL, 3.13 mmol) were dissolved in ACN (5 mL) and heated in the microwave for 10 minutes at 100° C. The volatiles were removed under reduced pressure. The residue was dissolved in DCM (20 mL) and washed with aqueous HCl (1 M) (2×5 mL) and brine (5 mL). The organic layer was concentrated to dryness and the residue was purified using silica gel chromatography (ethyl acetate in heptane from 5 to 100%) yielding compound 42 as a sticky oil (361 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.73-1.90 (m, 1H), 2.03-2.16 (m, 1H), 2.22 (s, 3H), 2.27-2.63 (m, 2H), 3.37-3.56 (m, 3H), 3.58-3.84 (m, 5H), 6 3.85-3.98 (m, 1H), 7.11 (t, J=9.1 Hz, 1H), 7.44-7.54 (m, 1H), 7.56-7.77 (m, 2H), 10.22 (br. s., 1H).

The racemic mixture 42 was separated in enantiomers by Prep SFC (Stationary phase: Chiralcel Diacel OJ 20×250 mm), mobile phase: CO₂, MeOH with 0.2% iPrNH₂). OJ-H 250 mm×4.6 mm, Flow: 5 mL/min, mobile phase: 10% MeOH (containing 0.2% iPrNH₂) hold 4 min. Rt: 42a: 3.66 min, 42b: 4.26 min.

Compound 43: N-(4-fluoro-3-methyl-phenyl)-3-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]-3-azabicyclo[3.1.0]hexane-1-carboxamide

Ethyl 3-benzyl-3-azabicyclo[3.1.0]hexane-1-carboxylate (synthesis described in WO201233956A1) (1.03 g, 4.2 mmol) was dissolved in THF. Water (10 mL) and LiOH (0.50 g, 21 mmol) were added to the reaction mixture which was stirred at room temperature for 12 hours. The reaction mixture was heated at reflux for 48 hours. The reaction mixture was evaporated to dryness. Azeotropic removal of water with toluene (2×20 mL) to obtain a crude which was used as such in the next step.

The crude mentioned above was suspended in DCM (50 mL). Triethylamine hydrochloride (5.78 g, 42.0 mmol), 4-fluoro-3-methyl-aniline (788 mg, 6.3 mmol) and HATU were added. The reaction mixture was stirred at RT for 2 hours. DMF (100 mL) and 4-fluoro-3-methyl-aniline (525 mg, 4.2 mmol) were added and the reaction mixture was stirred for 72 hours. The reaction mixture was diluted with DCM (100 mL) washed with saturated aqueous sodium bicarbonate (2×50 mL), dried (Na₂SO₄), filtered and evaporated. The crude was purified using silica gel column chromatography (ethyl acetate in heptane from 0 to 100%) to afford 3-benzyl-N-(4-fluoro-3-methyl-phenyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide (420 mg) as colorless sticky oil which was used as such in the next step. Method C; Rt: 1.17 min. m/z: 325.2 (M+H)⁺ Exact mass: 324.1

3-benzyl-N-(4-fluoro-3-methyl-phenyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide (400 mg) was dissolved in MeOH (50 mL) and 10% Pd on charcoal (262 mg) was added. This mixture was hydrogenated at room temperature at a H₂ pressure of 1 atm for 60 minutes. The solids were filtered off and the filtrate was evaporated under reduced pressure to afford (1S,5S)—N-(4-fluoro-3-methyl-phenyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide (282 mg) as a colorless oil. Method C; Rt: 0.60 min. m/z: 235.2 (M+H)⁺ Exact mass: 234.1.

N-(4-fluoro-3-methyl-phenyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide (141 mg, 0.58 mmol), (2-hydroxyphenyl)N-[(3S)-tetrahydrofuran-3-yl]sulfamate (180 mg, 0.70 mmol) and triethylamine (0.16 mL, 1.16 mmol) were dissolved in ACN (3 mL) and heated in the microwave for 10 minutes at 100° C. The volatiles were removed under reduced pressure. The residue was dissolved in DCM (20 mL) and washed with aqueous HCl (1 M) (2×5 mL) and brine (5 mL). The organic layer was concentrated to dryness and the residue was purified using silica gel chromatography (ethyl acetate in heptane from 30 to 100%) yielding compound 43 as a sticky oil (138 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (t, J=4.6 Hz, 1H), 1.41 (dd, J=8.1, 4.8 Hz, 1H), 1.76-1.86 (m, 1H), 2.03-2.14 (m, 1H), 2.17 (ddd, J=8.5, 5.0, 3.4 Hz, 1H), 2.20 (d, J=1.6 Hz, 3H), 3.27-3.38 (m, 2H), 3.50 (dd, J=8.9, 4.4 Hz, 1H), 3.56 (dd, J=9.3, 2.8 Hz, 1H), 3.62-3.66 (m, 1H), 3.64-3.69 (m, 1H), 3.73-3.80 (m, 2H), 3.81-3.89 (m, 1H), 7.05 (t, J=9.3 Hz, 1H), 7.42 (ddd, J=8.7, 4.6, 2.8 Hz, 1H), 7.50 (dd, J=7.3, 2.4 Hz, 1H), 9.30 (s, 1H). Method C; Rt: 0.83 min. m/z: 401.3 (M+NH₄)⁺ Exact mass: 383.1.

Compound 44: (3S)—N-(3,4-difluorophenyl)-1-[(3-methyloxetan-3-yl)sulfamoyl]pyrrolidine-3-carboxamide

(3S)—N-(3,4-difluorophenyl)pyrrolidine-3-carboxamide hydrochloride was prepared similarly as (3S)—N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide hydrochloride using 3,4-difluoroaniline instead of 4-fluoro-3-methylaniline. Compound 44 was prepared similarly as compound 34. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.60 (s, 3H), 2.00-2.22 (m, 2H), 3.11-3.30 (m, 4H), 3.49 (dd, J=9.6, 8.0 Hz, 1H), 4.21 (d, J=6.4 Hz, 2H), 4.65 (d, J=5.9 Hz, 2H), 7.25-7.33 (m, 1H), 7.38 (dt, J=10.5, 9.1 Hz, 1H), 7.63 (s, 1H), 7.78 (ddd, J=13.3, 7.5, 2.5 Hz, 1H), 10.28 (s, 1H). Method C; Rt: 0.78 min. m/z: 393.1 (M+NH₄)⁺ Exact mass: 375.1.

Compound 45: (3S)—N-(3,4-difluorophenyl)-1-[[(1R)-1-methylpropyl]sulfamoyl]pyrrolidine-3-carboxamide

(3S)—N-(3,4-difluorophenyl)pyrrolidine-3-carboxamide hydrochloride was prepared similarly as (3S)—N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide hydrochloride using 3,4-difluoroaniline instead of 4-fluoro-3-methylaniline. Compound 45 was prepared similarly as compound 34 using (R)-(−)-2-aminobutane instead of 3-methyl-3-oxetanamine hydrochloride (1:1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.86 (t, J=7.5 Hz, 3H), 1.10 (d, J=6.6 Hz, 3H), 1.31-1.51 (m, 2H), 1.98-2.21 (m, 2H), 3.10-3.29 (m, 5H), 3.47 (dd, J=9.6, 8.0 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 7.24-7.32 (m, 1H), 7.38 (dt, J=10.6, 9.1 Hz, 1H), 7.78 (ddd, J=13.3, 7.5, 2.5 Hz, 1H), 10.26 (s, 1H). Method C; Rt: 0.95 min. m/z: 362.2 (M+H)⁺ Exact mass: 361.1.

Compound 46: (3S)—N-(3,4-difluorophenyl)-1-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]pyrrolidine-3-carboxamide

(3S)—N-(3,4-difluorophenyl)pyrrolidine-3-carboxamide hydrochloride was prepared similarly as (3S)—N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide hydrochloride using 3,4-difluoroaniline instead of 4-fluoro-3-methylaniline. Compound 46 was prepared similarly as compound 34 using (S)-(−)-3-aminotetrahydrofuran-4-toluene-sulfonate instead of 3-methyl-3-oxetanamine hydrochloride (1:1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.75-1.86 (m, 1H), 2.01-2.12 (m, 2H), 2.12-2.22 (m, 1H), 3.12-3.30 (m, 4H), 3.44-3.54 (m, 2H), 3.65 (td, J=8.0, 5.9 Hz, 1H), 3.71-3.81 (m, 2H), 3.81-3.92 (m, 1H), 7.24-7.33 (m, 1H), 7.38 (dt, J=10.6, 9.0 Hz, 1H), 7.47 (br. s., 1H), 7.78 (ddd, J=13.3, 7.5, 2.5 Hz, 1H), 10.28 (br. s., 1H). Method C; Rt: 0.80 min. m/z: 376.0 (M+H)⁺ Exact mass: 375.1.

Compound 47: (3S)—N-(4-fluoro-3-methyl-phenyl)-1-[[3-(2-hydroxyethyl)oxetan-3-yl]sulfamoyl]pyrrolidine-3-carboxamide

Compound 47 was prepared similarly as compound 34 using 2-(3-aminooxetan-3-yl)ethanol instead of 3-methyl-3-oxetanamine hydrochloride (1:1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.01-2.18 (m, 4H), 2.20 (d, J=1.8 Hz, 3H), 3.10-3.30 (m, 4H), 3.51 (dd, J=9.5, 8.1 Hz, 1H), 3.56-3.64 (m, 2H), 4.39 (d, J=6.6 Hz, 2H), 4.47 (t, J=5.1 Hz, 1H), 4.64 (d, J=6.4 Hz, 2H), 7.07 (t, J=9.2 Hz, 1H), 7.36-7.43 (m, 1H), 7.48-7.55 (m, 2H), 10.02 (s, 1H). Method C; Rt: 0.72 min. m/z: 402.1 (M+H)⁺ Exact mass: 401.1.

Compound 48: (3S)—N-(4-fluoro-3-methyl-phenyl)-1-[(1-methyl-2-oxo-pyrrolidin-3-yl)sulfamoyl]pyrrolidine-3-carboxamide

Compound 48 was prepared similarly as compound 34 using 3-amino-1-methyl-2-pyrrolidinone instead of 3-methyl-3-oxetanamine hydrochloride (1:1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.71-1.85 (m, 1H), 2.00-2.10 (m, 1H), 2.10-2.18 (m, 1H), 2.20 (d, J=1.8 Hz, 3H), 2.29-2.40 (m, 1H), 2.74 (s, 3H), 3.12-3.30 (m, 5H), 3.33-3.41 (m, 1H), 3.55 (td, J=8.7, 3.9 Hz, 1H), 3.98 (qd, J=9.1, 5.8 Hz, 1H), 7.06 (t, J=9.1 Hz, 1H), 7.35-7.43 (m, 1H), 7.52 (d, J=7.0 Hz, 1H), 7.56 (dd, J=13.8, 8.9 Hz, 1H), 9.99 (d, J=7.5 Hz, 1H). Method C; Rt: 0.75 min. m/z: 399.2 (M+H)⁺ Exact mass: 398.1.

Compound 49: (3S)—N-(4-fluoro-3-methyl-phenyl)-1-(6-oxa-2-azaspiro[3.3]heptan-2-ylsulfonyl)pyrrolidine-3-carboxamide

Compound 49 was prepared similarly as compound 34 using 2-oxa-6-azaspiro[3.3]heptane instead of 3-methyl-3-oxetanamine hydrochloride (1:1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.99-2.18 (m, 2H), 2.20 (d, J=1.5 Hz, 3H), 3.09-3.21 (m, 2H), 3.22-3.30 (m, 1H), 3.33-3.40 (m, 1H), 3.51 (dd, J=9.7, 7.9 Hz, 1H), 4.00 (s, 4H), 4.65 (s, 4H), 7.07 (t, J=9.2 Hz, 1H), 7.35-7.44 (m, 1H), 7.51 (dd, J=7.0, 2.4 Hz, 1H), 10.02 (s, 1H). Method C; Rt: 0.81 min. m/z: 384.1 (M+H)⁺ Exact mass: 383.1.

Compound 50: (3S)—N-(4-fluoro-3-methyl-phenyl)-1-[(1-methyl-5-oxo-pyrrolidin-3-yl)sulfamoyl]pyrrolidine-3-carboxamide

Compound 50 was prepared similarly as compound 34 using 4-amino-1-methyl-pyrrolidin-2-one hydrochloride instead of 3-methyl-3-oxetanamine hydrochloride (1:1). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.00-2.11 (m, 1H), 2.11-2.19 (m, 1H), 2.20 (d, J=1.8 Hz, 3H), 2.23 (d, J=5.5 Hz, 1H), 2.56 (dd, J=16.8, 8.5 Hz, 1H), 2.69 (d, J=4.2 Hz, 3H), 3.10-3.20 (m, 1H), 3.20-3.26 (m, 2H), 3.26-3.30 (m, 2H), 3.43-3.52 (m, 1H), 3.55-3.64 (m, 1H), 3.90-4.02 (m, 1H), 7.07 (t, J=9.1 Hz, 1H), 7.33-7.44 (m, 1H), 7.51 (dd, J=7.0, 2.6 Hz, 1H), 7.63 (dd, J=7.0, 3.1 Hz, 1H), 10.01 (d, J=2.6 Hz, 1H). Method C; Rt: 0.72 min. m/z: 399.2 (M+H)⁺ Exact mass: 398.1.

Compound 51: methyl N-[(2R)-2-[[(3S)-3-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrolidin-1-yl]sulfonylamino]propyl]carbamate

tert-butyl N-[(2R)-2-[[(3S)-3-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrolidin-1-yl]sulfonylamino]propyl]carbamate was prepared similarly as compound 34 using N-[(2R)-2-aminopropyl]-carbamic acid 1,1-dimethylethyl ester instead of 3-methyl-3-oxetanamine hydrochloride (1:1).

tert-butyl N-[(2R)-2-[[(3S)-3-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrolidin-1-yl]sulfonylamino]propyl]carbamate (2.07 g, 4.52 mmol) was dissolved in DCM (25 mL). HCl (6M in iPrOH) (25 mL) was added and the reaction mixture was stirred overnight at room temperature. The volatiles were removed under reduced pressure and the residue was used as such in the next step.

The crude mentioned above was dissolved in DCM (20 mL) together with DIPEA (3.11 mL, 18.1 mmol). Methyl chloroformate (0.52 mL, 6.77 mmol) was added drop wise and the reaction mixture was stirred overnight at room temperature. The volatiles were removed under reduced pressure and the residue was purified on silica using a heptane to EtOAc gradient yielding the product as an oil which solidified on standing to a white powder (394 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07 (d, J=6.6 Hz, 3H), 1.99-2.18 (m, 2H), 2.20 (d, J=1.8 Hz, 3H), 2.93 (dt, J=13.5, 6.8 Hz, 1H), 3.02-3.30 (m, 5H), 3.32 (s, 3H), 3.34-3.39 (m, 1H), 3.48 (dd, J=9.5, 8.4 Hz, 1H), 7.02-7.10 (m, 2H), 7.12 (t, J=5.9 Hz, 1H), 7.35-7.42 (m, 1H), 7.51 (dd, J=7.0, 2.4 Hz, 1H), 10.00 (s, 1H). Method C; Rt: 0.81 min. m/z: 417.1 (M+H)⁺ Exact mass: 416.2. [α]_(D) ²⁰: −12.9° (c 0.52 w/v %, DMF).

BIOLOGICAL EXAMPLES Anti-HBV Activity of Compounds of Formula (I)

The anti-HBV activity was measured using a stable transfected cell line, HepG2.2.15. This cell line was described to secrete relatively consistent high levels of HBV virion particles, which have been shown to cause both acute and chronic infection and disease in chimpanzees. For the antiviral, assay cells were treated twice for three days with serially diluted compound in 96-well plates in duplicate. After 6 days of treatment the antiviral activity was determined by quantification of purified HBV DNA from secreted virions using realtime PCR and an HBV specific primer set and probe.

The anti HBV activity was also measured using the HepG2.117 cell line, a stable, inducibly HBV producing cell line, which replicates HBV in the absence of doxicycline (Tet-off system). For the antiviral assay, HBV replication was induced, followed by a treatment with serially diluted compound in 96-well plates in duplicate. After 3 days of treatment, the antiviral activity was determined by quantification of intracellular HBV DNA using realtime PCR and an HBV specific primer set and probe.

Cytotoxicity of the compounds was tested using HepG2 cells, incubated for 4 days in the presence of compounds. The viability of the cells was assessed using a Resazurin assay. Results are displayed in Table 1.

TABLE 1 HepG2 HepG2 HepG2 Co. 2.15 117 4 days No. EC50 (μM) EC50 (μM) CC50 (μM)  1 0.94 0.72 >25  2 1.32 0.31 >25  3 >25 1.49 >25  4 16.4 10.7 >25  5 9.1 2.0 >25  6 1.9 0.62 >25  7 13.5 4.7 >25  8 0.58 0.33 >25  9 1.4 0.95 >25 10 4.3 0.76 22.9 11 7.0 3.1 >25 12 4.1 2.3 >25 13 4.6 3.4 >25 14 1.9 1.5 >25 15 12.5 14.7 >25 16 3.5 2.5 >25 17 5.9 5.9 >25 18 5.8 5.3 >25 19 8.4 2.9 >25 20 16.1 4.0 >25 21 5.4 2.7 >25 22 13.6 8.6 >25 23 0.96 1.4 >25 24 0.50 0.33 >25 24a 1.4 1.7 >25 24b 0.11 0.061 >25 25 5.5 0.43 >25 26 4.4 0.41 >25 27 2.8 2.0 >25 28 2.0 3.9 >25 29 13.7 18.9 >25 29a >25 >25 >25 29b 18.3 6.9 >25 30 0.61 4.7 >25 31 0.45 0.47 >25 32 0.18 0.12 >25 33 0.15 0.075 >25 34 0.11 0.11 >25 35a 0.563 0.228 >25 35b >5 >5 >25 36a 2.39 2.65 >25 36b 0.46 0.38 >25 37 0.27 0.53 >25 38 3.65 2.07 >25 39 0.15 >25 40 0.29 0.12 >25 41 0.53 0.42 >25 42a >5 >5 >25 42b 3.25 1.69 >25 43 0.58 0.85 >25 44 0.61 0.42 >25 45 3.25 0.54 >25 46 0.60 0.24 >25 47 0.065 0.091 >25 48 1.37 0.57 >25 49 1.49 0.95 >25 50 0.35 0.46 >25 51 0.15 0.057 >25 52 0.55 0.46 >25 

The invention claimed is:
 1. A compound of Formula (I)

or a stereoisomer or tautomeric form thereof, wherein

X is —(SO₂)—, and R⁴ is selected from the group consisting of —NR⁵R⁶, C₁-C₆alkyl, and a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, said 3-7 membered saturated ring or C₁-C₆alkyl optionally substituted with one or more substituents each independently selected from the group consisting of hydrogen, fluoro, C₁-C₄alkyloxy, OH, oxo, C₁-C₄alkyl, and cyclopropyl; or X is a single bond, and R⁴ is —C(═O)OR⁷; R¹, R² and R³ are each independently selected from the group consisting of hydrogen, halogen, CN, CHF₂, CH₂F, CF₃, C₁-C₃alkyl and cyclopropyl; R⁵ is hydrogen or methyl; R⁶ is C₁-C₆alkyl or a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, said 3-7 membered saturated ring and C₁-C₆alkyl each independently optionally substituted with one or more substituents selected from the group consisting of hydrogen, fluoro, CN, OH, oxo, —NHC(═O)O—C₁-C₄alkyl, and C₁-C₄alkyl optionally substituted with one or more substituents selected from the group consisting of R⁸ fluoro, C₁-C₄alkyloxy,

R⁷ is C₁-C₆alkyl or a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N; and R⁸ is selected from the group consisting hydrogen, OH, C₁-C₄alkyl and CN; or a pharmaceutically acceptable salt or a solvate thereof.
 2. A compound according to claim 1 wherein

represents


3. A compound according to claim 1 represented by Formula (Ib)

or a stereoisomer or tautomeric form, or a pharmaceutically acceptable salt or a solvate thereof.
 4. A compound according to claim 1, wherein R¹ is fluoro or methyl, and R² is fluoro.
 5. A compound according to claim 1, wherein X is —(SO₂)—, and R⁴ is —NR⁵R⁶.
 6. A compound according to claim 1, wherein R⁴ is a 3-7 membered saturated ring optionally containing one oxygen.
 7. A compound according to claim 1, wherein R⁶ is a branched C₃-C₆alkyl optionally substituted with one or more fluoro, or R⁶ is a C₃-C₆cycloalkyl wherein said C₃-C₆cycloalkyl is substituted with one or more fluoro or C₁-C₄ alkyl substituted with one or more fluoro.
 8. A compound according to claim 7 wherein, R⁶ is a branched C₃-C₆alkyl substituted with one or more fluoro.
 9. A method of treating an HBV infection comprising administering a therapeutically effective amount of at least one compound of claim
 1. 10. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier.
 11. A product containing (a) a compound of Formula (I) as defined in claim 1, and (b) HBV inhibitor, as a combined preparation for simultaneous, separate or sequential use in the treatment of HBV infection.
 12. A compound according to claim 1, wherein at least one of R¹, R² and R³ is fluoro, and one other of R′, R² and R³ is selected from the group consisting of hydrogen, halogen, CN, CHF₂, CH₂F, CF₃, C₁-C₃alkyl and cyclopropyl.
 13. A compound according to claim 1, wherein R¹ is methyl and R² is fluoro.
 14. A compound according to claim 1, having a structure corresponding to


15. A compound according to claim 1, having a structure corresponding to


16. A compound according to claim 1, having a structure corresponding to


17. A compound according to claim 1, wherein R¹ is methyl and R² is fluoro;

and X is —(SO₂)—.
 18. A compound according to claim 1, wherein

is selected from the group consisting of


19. A compound according to claim 1, wherein said compound is selected from the group consisting of N-(4-fluoro-3-methyl-phenyl)-1-isobutylsulfonyl-pyrrolidine-3-carboxamide, (3S)—N-(4-fluoro-3-methyl-phenyl)-1-isobutylsulfonyl-pyrrolidine-3-carboxamide, (3R)—N-(4-fluoro-3-methyl-phenyl)-1-isobutylsulfonyl-pyrrolidine-3-carboxamide, (3S)—N-(4-fluoro-3-methyl-phenyl)-1-propylsulfonyl-pyrrolidine-3-carboxamide, (3S)-1-(cyclopropylmethylsulfonyl)-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide, (3S)—N-(4-fluoro-3-methyl-phenyl)-1-tetrahydropyran-4-ylsulfonyl-pyrrolidine-3-carboxamide, (3S)-1-cyclopentylsulfonyl-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide, (3S)-1-(2-ethylcyclopropyl)sulfonyl-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide, (3S)—N-(4-fluoro-3-methyl-phenyl)-1-sec-butylsulfonyl-pyrrolidine-3-carboxamide, isobutyl (3S)-3-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrolidine-1-carboxylate, (1 S,5S)—N-(4-fluoro-3-methyl-phenyl)-3-isobutylsulfonyl-3-azabicyclo[3.1.0]hexane-1-carboxamide, N-(4-fluoro-3-methyl-phenyl)-1-isobutylsulfonyl-indoline-3-carboxamide, N-(4-fluoro-3-methyl-phenyl)-1-isobutylsulfonyl-3-methyl-pyrrolidine-3-carboxamide, N-(4-fluoro-3-methyl-phenyl)-7-isobutylsulfonyl-7-azabicyclo[2.2.1]heptane-3-carboxamide, (3S)—N-(4-fluoro-3-methyl-phenyl)-1-(isobutylsulfamoyl)pyrrolidine-3-carboxamide, (3S)—N-(4-fluoro-3-methyl-phenyl)-1-(isopropylsulfamoyl)pyrrolidine-3-carboxamide, (3S)—N-(4-fluoro-3-methyl-phenyl)-1-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]pyrrolidine-3-carboxamide, (3S)—N-(4-fluoro-3-methyl-phenyl)-1-[(3-methyloxetan-3-yl)sulfamoyl]pyrrolidine-3-carboxamide, 3-fluoro-N-(4-fluoro-3-methyl-phenyl)-1-(isopropylsulfamoyl)pyrrolidine-3-carboxamide, N-(4-fluoro-3-methyl-phenyl)-2-(isopropylsulfamoyl)-2-azabicyclo[3.1.0]hexane-4-carboxamide, (3S)—N-(4-fluoro-3-methyl-phenyl)-1-[[(1R,2R)-2-hydroxyindan-1-yl]sulfamoyl]pyrrolidine-3-carboxamide, tert-butyl N-[2-[[(3S)-3-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrolidin-1-yl]sulfonylamino]propyl]carbamate, (3S)—N-(4-fluoro-3-methyl-phenyl)-1-[[(1R)-2-hydroxy-1-methyl-ethyl]sulfamoyl]pyrrolidine-3-carboxamide, (3S)-1-[(2-cyano-1-methyl-ethyl)sulfamoyl]-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide, trans-N-(4-fluoro-3-methyl-phenyl)-1-(isopropylsulfamoyl)-4-methyl-pyrrolidine-3-carboxamide, 3-fluoro-N-(4-fluoro-3-methyl-phenyl)-1-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]pyrrolidine-3-carboxamide, N-(4-fluoro-3-methyl-phenyl)-3-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]-3-azabicyclo[3.1.0]hexane-1-carboxamide, (3S)—N-(3,4-difluorophenyl)-1-[(3-methyloxetan-3-yl)sulfamoyl]pyrrolidine-3-carboxamide, (3S)—N-(3,4-difluorophenyl)-1-[[(1R)-1-methylpropyl]sulfamoyl]pyrrolidine-3-carboxamide, (3S)—N-(3,4-difluorophenyl)-1-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]pyrrolidine-3-carboxamide, (3S)—N-(4-fluoro-3-methyl-phenyl)-1-[[3-(2-hydroxyethyl)oxetan-3-yl]sulfamoyl]pyrrolidine-3-carboxamide, (3S)—N-(4-fluoro-3-methyl-phenyl)-1-[(1-methyl-2-oxo-pyrrolidin-3-yl)sulfamoyl]pyrrolidine-3-carboxamide, (3S)—N-(4-fluoro-3-methyl-phenyl)-1-(6-oxa-2-azaspiro[3.3]heptan-2-ylsulfonyl)pyrrolidine-3-carboxamide, (3S)—N-(4-fluoro-3-methyl-phenyl)-1-[(1-methyl-5-oxo-pyrrolidin-3-yl)sulfamoyl]pyrrolidine-3-carboxamide, and methyl N-[(2R)-2-[[(3S)-3-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrolidin-1-yl]sulfonylamino]propyl]carbamate. 